Method for synthesizing furanosteroids
a technology of furanosteroids and synthetic methods, applied in the field of synthetic methods for furanosteroids, can solve the problems of many difficulties in the analysis of wortmannin and viridin derivatives
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example 1
Synthesis of Alkyne Oxazoles
[0028]Using a general procedure for converting salicylaldehyde derivatives to a wide variety of o-substituted phenols (Van De Water, et al. (2000) J. Am. Chem. Soc. 122(27):6502), alkyne oxazoles were produced as illustrated in Scheme 2.
[0029]
[0030]Parent compound 3 was converted to the Boc-derivative 4. In a very efficient sequence, treatment of 4 with 1.05 eq of MeLi generated the reactive o-quinone methide 5, by a pathway involving nucleophilic addition to the aldehyde, followed by intramolecular transfer of the Boc group and 1,4-elimination. Quenching with the Grignard reagent derived from trimethylsilylacetylene followed by triflation then gave a 74% overall yield of the desired triflate derivative 7 on 95 mmol scales (>20 grams). With gram quantities of 7 in hand, a straightforward, three-step sequence was developed to produce the alkyne oxazole 11a. This three-step process involved (i, ii) elaboration to the corresponding boronic acid 10 and (iii) ...
example 2
Synthesis of Viridin Model
[0056]Toward the synthesis of a viridin model, two approaches were employed. In the first of these, the alkyne oxazole 11c (R=cis-HC═CHCO2Et; Scheme 3) was employed. Alkyne oxazole 11c was prepared in 65% yield by Sonogashira coupling of 11b (R═H) with ethyl cis-iodoacrylate. Upon heating in o-xylene (140° C.), 11c was transformed to a mixture of 12c-15c, in a combined yield of 59% at 73% conversion (Scheme 3). The formation of 14c and 15c could be somewhat lessened by thorough degassing and employing antioxidants. In general, though, it was expeditious to allow oxidation to proceed, since both 14c and 15c functioned as convenient and stable sources of the parent phenol 13 and related derivatives. For example, employing 14c allowed for the preparation of the saturated ester derivative 17 by a simple two step sequence including catalytic hydrogenation (14c→16; the structure of 14c was confirmed by X-ray analysis of the dihydro derivative 16 obtained upon cat...
example 3
Synthesis of Viridin Furanosteroids
[0082]Using the same approach for synthesis of 19-syn, a family of viridin furanosteroids (1a-1d) can be produced.
[0083]
[0084]For example, thermolysis of alkyne oxazole 22, produced from indanone derivative 21, followed by in situ silylation leads directly to phenol derivative 23, following the now well-established pathway of Diels-Alder / retro-Diels-Alder reaction / tautomerization (Scheme 5). Compound 23 is then employed to construct aldehydes of general structure 24 and subsequently furanosteroids 25. For X═O, 25 affords demethoxyviridin (26) upon hydrolysis. For X=β-OH hydrolysis affords demethoxyviridiol (27). As precedent for the transformation of 22 to 23, model system 11e gave a 50% overall yield of the furanoester 28 employing an analogous sequence.
[0085]
[0086]The synthesis of 22 begins with the commercially available (and easily prepared on 50 gram scales) indanone derivative 21 (Scheme 6; Kelly, et al. (1988) J. Am. Chem. Soc. 110:6471). Th...
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